Ten genetic loci for colorectal cancer have been identified from published genome wide association (GWA) studies of colorectal cancer (CRC) and have been robustly replicated in populations of European ancestry. We hypothesize that additional novel risk loci will be identified by joint analyses in which data of approximately 7,000 cases and 7,000 controls from the five existing GWA studies are combined and validated in additional independent samples of cases and controls. In addition, combining genotypic data will allow analyses to be stratified according to demographic and clinico-pathological parameters, and permit studies to identify gene-gene interaction effects that specifically increase CRC risk. Genetic loci identified by pooled analyses will be examined in more detail here in Area 1 Discovery Expansion and Replication as well as Area 3 Epidemiologic Studies in additional case-control studies and nested case-control studies derived from two prospective cohort studies (Melbourne and ACS Cancer Prevention Study II Nutrition Cohort) to determine the extent that these and previously identified common variants are associated with risk. Finally, follow-up fine mapping studies, together with functional analyses in Area 2 - Biological Studies, will help to identify the specific causal factors that influence risk of CRC. The goal of this proposal is therefore to establish find new genetic associations through pooled analyses, independently replicate these findings to confirm genotype-phenotype associations, fine-map association signals, and pursue gene-gene interactions with high-density data. The proposed study will comprehensively and efficiently identify new genes that predispose to colorectal cancer. This work has considerable potential to reveal new important targets for cancer prevention and treatment.